Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection

Adam Schaffner; Xianting Li; Yacob Gomez-Llorente; Emmanouela Leandrou; Anna Memou; Nicolina Clemente; Chen Yao; Farinaz Afsari; Lianteng Zhi; Nina Pan; Keita Morohashi; Xiaoluan Hua; Ming-Ming Zhou; Chunyu Wang; Hui Zhang; Shu G. Chen; Christopher John Hazell Elliott; Hardy Rideout; Iban Ubarretxena-Belandia; Zhenyu Yue

doi:10.1038/s41422-019-0153-8

Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection

Adam Schaffner, Xianting Li, Yacob Gomez-Llorente, Emmanouela Leandrou, Anna Memou, Nicolina Clemente, Chen Yao, Farinaz Afsari, Lianteng Zhi, Nina Pan, Keita Morohashi, Xiaoluan Hua, Ming-Ming Zhou, Chunyu Wang, Hui Zhang, Shu G. Chen, Christopher John Hazell Elliott, Hardy Rideout, Iban Ubarretxena-Belandia, Zhenyu Yue

Biology

Research output: Contribution to journal › Article › peer-review

Abstract

Missense mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) cause the majority of familial and some sporadic forms of Parkinson’s disease (PD). The hyperactivity of LRRK2 kinase induced by the pathogenic mutations underlies neurotoxicity, promoting the development of LRRK2 kinase inhibitors as therapeutics. Many potent and specific small molecule LRRK2 inhibitors have been reported with promise. However, nearly all inhibitors are ATP competitive – some with unwanted side effects and unclear clinical outcome - alternative types of LRRK2 inhibitors are lacking. Herein we find 5’-deoxyadenosylcobalamin (AdoCbl), a physiological form of the essential micronutrient vitamin B12 as a mixed-type allosteric inhibitor of LRRK2 kinase activity. Multiple assays show that AdoCbl directly binds LRRK2, leading to the alterations of protein conformation and ATP binding in LRRK2. STD-NMR analysis of a LRRK2 homologous kinase reveals the contact sites in AdoCbl that interface with the kinase domain. Furthermore, we provide evidence that AdoCbl modulates LRRK2 activity through disruption of LRRK2 dimerization. Treatment with AdoCbl inhibits LRRK2 kinase activity in cultured cells and brain tissue, and importantly prevents neurotoxicity in primary rodent cultures as well as in transgenic C. elegans and D. melanogaster expressing LRRK2 disease variants. Finally, AdoCbl alleviates deficits in dopamine release sustainability caused by LRRK2 disease variants in mouse models. Our study uncovers vitamin B12 as a novel class of LRRK2 kinase modulator with a distinct mechanism, which can be harnessed to develop new LRRK2-based PD therapeutics in the future

Original language	English
Pages (from-to)	313-329
Journal	Cell Research
Volume	29
Issue number	4
Early online date	11 Mar 2019
DOIs	https://doi.org/10.1038/s41422-019-0153-8
Publication status	Published - Apr 2019

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© 2019 Springer Nature Publishing AG. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

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10.1038/s41422-019-0153-8

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Schaffner, A., Li, X., Gomez-Llorente, Y., Leandrou, E., Memou, A., Clemente, N., Yao, C., Afsari, F., Zhi, L., Pan, N., Morohashi, K., Hua, X., Zhou, M.-M., Wang, C., Zhang, H., Chen, S. G., Elliott, C. J. H., Rideout, H., Ubarretxena-Belandia, I., & Yue, Z. (2019). Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection. Cell Research, 29(4), 313-329. https://doi.org/10.1038/s41422-019-0153-8

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title = "Vitamin B12 modulates Parkinson{\textquoteright}s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection",

abstract = "Missense mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) cause the majority of familial and some sporadic forms of Parkinson{\textquoteright}s disease (PD). The hyperactivity of LRRK2 kinase induced by the pathogenic mutations underlies neurotoxicity, promoting the development of LRRK2 kinase inhibitors as therapeutics. Many potent and specific small molecule LRRK2 inhibitors have been reported with promise. However, nearly all inhibitors are ATP competitive – some with unwanted side effects and unclear clinical outcome - alternative types of LRRK2 inhibitors are lacking. Herein we find 5{\textquoteright}-deoxyadenosylcobalamin (AdoCbl), a physiological form of the essential micronutrient vitamin B12 as a mixed-type allosteric inhibitor of LRRK2 kinase activity. Multiple assays show that AdoCbl directly binds LRRK2, leading to the alterations of protein conformation and ATP binding in LRRK2. STD-NMR analysis of a LRRK2 homologous kinase reveals the contact sites in AdoCbl that interface with the kinase domain. Furthermore, we provide evidence that AdoCbl modulates LRRK2 activity through disruption of LRRK2 dimerization. Treatment with AdoCbl inhibits LRRK2 kinase activity in cultured cells and brain tissue, and importantly prevents neurotoxicity in primary rodent cultures as well as in transgenic C. elegans and D. melanogaster expressing LRRK2 disease variants. Finally, AdoCbl alleviates deficits in dopamine release sustainability caused by LRRK2 disease variants in mouse models. Our study uncovers vitamin B12 as a novel class of LRRK2 kinase modulator with a distinct mechanism, which can be harnessed to develop new LRRK2-based PD therapeutics in the future",

author = "Adam Schaffner and Xianting Li and Yacob Gomez-Llorente and Emmanouela Leandrou and Anna Memou and Nicolina Clemente and Chen Yao and Farinaz Afsari and Lianteng Zhi and Nina Pan and Keita Morohashi and Xiaoluan Hua and Ming-Ming Zhou and Chunyu Wang and Hui Zhang and Chen, {Shu G.} and Elliott, {Christopher John Hazell} and Hardy Rideout and Iban Ubarretxena-Belandia and Zhenyu Yue",

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Schaffner, A, Li, X, Gomez-Llorente, Y, Leandrou, E, Memou, A, Clemente, N, Yao, C, Afsari, F, Zhi, L, Pan, N, Morohashi, K, Hua, X, Zhou, M-M, Wang, C, Zhang, H, Chen, SG, Elliott, CJH, Rideout, H, Ubarretxena-Belandia, I & Yue, Z 2019, 'Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection', Cell Research, vol. 29, no. 4, pp. 313-329. https://doi.org/10.1038/s41422-019-0153-8

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T1 - Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection

AU - Schaffner, Adam

AU - Li, Xianting

AU - Gomez-Llorente, Yacob

AU - Leandrou, Emmanouela

AU - Memou, Anna

AU - Clemente, Nicolina

AU - Yao, Chen

AU - Afsari, Farinaz

AU - Zhi, Lianteng

AU - Pan, Nina

AU - Morohashi, Keita

AU - Hua, Xiaoluan

AU - Zhou, Ming-Ming

AU - Wang, Chunyu

AU - Zhang, Hui

AU - Chen, Shu G.

AU - Elliott, Christopher John Hazell

AU - Rideout, Hardy

AU - Ubarretxena-Belandia, Iban

AU - Yue, Zhenyu

N1 - © 2019 Springer Nature Publishing AG. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

PY - 2019/4

Y1 - 2019/4

N2 - Missense mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) cause the majority of familial and some sporadic forms of Parkinson’s disease (PD). The hyperactivity of LRRK2 kinase induced by the pathogenic mutations underlies neurotoxicity, promoting the development of LRRK2 kinase inhibitors as therapeutics. Many potent and specific small molecule LRRK2 inhibitors have been reported with promise. However, nearly all inhibitors are ATP competitive – some with unwanted side effects and unclear clinical outcome - alternative types of LRRK2 inhibitors are lacking. Herein we find 5’-deoxyadenosylcobalamin (AdoCbl), a physiological form of the essential micronutrient vitamin B12 as a mixed-type allosteric inhibitor of LRRK2 kinase activity. Multiple assays show that AdoCbl directly binds LRRK2, leading to the alterations of protein conformation and ATP binding in LRRK2. STD-NMR analysis of a LRRK2 homologous kinase reveals the contact sites in AdoCbl that interface with the kinase domain. Furthermore, we provide evidence that AdoCbl modulates LRRK2 activity through disruption of LRRK2 dimerization. Treatment with AdoCbl inhibits LRRK2 kinase activity in cultured cells and brain tissue, and importantly prevents neurotoxicity in primary rodent cultures as well as in transgenic C. elegans and D. melanogaster expressing LRRK2 disease variants. Finally, AdoCbl alleviates deficits in dopamine release sustainability caused by LRRK2 disease variants in mouse models. Our study uncovers vitamin B12 as a novel class of LRRK2 kinase modulator with a distinct mechanism, which can be harnessed to develop new LRRK2-based PD therapeutics in the future

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Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection

Abstract

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Chris Elliott

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Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection

Abstract

Bibliographical note

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Chris Elliott

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